Maria Jimenez-Gonzalez

Behavioural adaptations to environmental threats are crucial for survival^1,2 and necessitate rapid deployment of energy reserves^3,4,5. The amygdala coordinates behavioural adaptations to threats⁶, but little is known about its involvement in underpinning metabolic adaptations. Here we show that acute stress activates medial amygdala (MeA) neurons that innervate the ventromedial hypothalamus (MeA^VMH neurons), which precipitates hyperglycaemia and hypophagia. The glycaemic actions of MeA^VMH neurons occur independently of adrenal or pancreatic glucoregulatory hormones. Using whole-body virus tracing, we identify a polysynaptic connection from MeA to the liver that promotes the rapid synthesis of glucose by hepatic gluconeogenesis. Repeated stress exposure disrupts MeA control of blood glucose, resulting in diabetes-like dysregulation of glucose homeostasis. Our findings reveal an amygdala–liver axis that regulates rapid glycaemic adaptations to stress and links recurrent stress to metabolic dysfunction.

Multiple sclerosis (MS) is a debilitating neurodegenerative disease with a rising prevalence. As an autoimmune disorder that damages myelin-producing cells, most current therapies focus on immunosuppression. However, impaired glucose metabolism is frequently observed in MS patients (Mathur et al.,) Metformin, a widely used diabetes drug, has shown promise in promoting myelin repair in preclinical models and is currently being investigated in clinical trials. It activates AMPK, a key regulator of energy metabolism, yet its effects on oligodendrocytes-the cells responsible for myelin production-and their precursors remain poorly understood.Mohanlall et al., explored metformin's influence on glucose metabolism and oligodendrocyte progenitor differentiation in young mice, as well as its effects in a chemical model of demyelination. Their study found that metformin significantly alters cellular metabolism and enhances the differentiation of precursors into oligodendrocytes, potentially improving myelin repair and function.Neurodegenerative diseases encompass a wide spectrum of disorders, many of which are driven by single pathogenic variants affecting neuronal energy production and mitochondrial metabolism. Studying these genetic mutations provides valuable insights into how glucose metabolism influences neurodegeneration.One of the studies in this topic characterized a novel pathogenic variant of the ACO2 gene, which encodes aconitase 2, a mitochondrial enzyme essential for the TCA cycle and mitochondrial DNA integrity. Mutations in ACO2 have been linked to severe neuropathologies, including infantile cerebellar retinal degeneration. Yang et al., identified new ACO2 variants in an infant patient with cerebellar retinal degeneration. Their analysis revealed compound heterozygous mutations, c.854A>G (p.Asn285Ser) and c.1183C>T (p.Arg395Cys), alongside alterations in metabolic, immune, and neurophysiological pathways. These findings suggest that ACO2 mutations impact more than just mitochondrial function, further highlighting their relevance to neurodegenerative processes.Another work presented in this topic, a thorough review by Santucci et al., examined the role of impaired brain glucose metabolism in Progressive Myoclonus Epilepsies (PMEs)-a group of rare inherited neurological disorders that lead to myoclonus jerks, seizures and progressive neurological decline. Specifically, the review focuses on the subgroup of neuronal ceroid lipofuscinoses (NCLs), where mutations disrupt genes essential for proper lysosomal function The authors discuss glucose hypometabolism as a hallmark of the disease and explore the potential of antidiabetic drugs like metformin and GLP-1 analogs in slowing neurodegeneration. Their review highlights the therapeutic potential of these treatments for PMEs, emphasizing the need for further research.Brain energy metabolism is profoundly influenced by alterations in the blood-brain barrier (BBB), which regulates the transport of nutrients, hormones, and other essential factors. Notably, reduced BBB integrity is frequently observed in Alzheimer's (AD) and Parkinson's disease (PD), contributing to cognitive decline. Lv et al., provide a comprehensive review of the role of platelets in increasing BBB permeability in the context of brain pathology. Their analysis sheds light on how vascular dysfunction contributes to neurodegeneration, emphasizing the importance of further investigation into BBB integrity and its therapeutic implications.The studies compiled in this research topic highlight the intricate relationship between metabolic dysfunction and neurodegeneration. They emphasize the need for an interdisciplinary approach to further explore the underlying mechanisms of this interaction and develop more targeted therapies, including the repurposing of existing metabolic disease treatments.

A lack of comprehensive mapping of ganglionic inputs into the pancreas and of technology for the modulation of the activity of specific pancreatic nerves has hindered the study of how they regulate metabolic processes. Here we show that the pancreas-innervating neurons in sympathetic, parasympathetic and sensory ganglia can be mapped in detail by using tissue clearing and retrograde tracing (the tracing of neural connections from the synapse to the cell body), and that genetic payloads can be delivered via intrapancreatic injection to target sites in efferent pancreatic nerves in live mice through optimized adeno-associated viruses and neural-tissue-specific promoters. We also show that, in male mice, the targeted activation of parasympathetic cholinergic intrapancreatic ganglia and neurons doubled plasma-insulin levels and improved glucose tolerance, and that tolerance was impaired by stimulating pancreas-projecting sympathetic neurons. The ability to map the peripheral ganglia innervating the pancreas and to deliver transgenes to specific pancreas-projecting neurons will facilitate the examination of ganglionic inputs and the study of the roles of pancreatic efferent innervation in glucose metabolism.

The central and peripheral nervous systems play critical roles in regulating pancreatic islet function and glucose metabolism. Over the last century, in vitro and in vivo studies along with examination of human pancreas samples have revealed the structure of islet innervation, investigated the contribution of sympathetic, parasympathetic and sensory neural pathways to glucose control, and begun to determine how the structure and function of pancreatic nerves are disrupted in metabolic disease. Now, state-of-the art techniques such as 3D imaging of pancreatic innervation and targeted in vivo neuromodulation provide further insights into the anatomy and physiological roles of islet innervation. Here, we provide a summary of the published work on the anatomy of pancreatic islet innervation, its roles, and evidence for disordered islet innervation in metabolic disease. Finally, we discuss the possibilities offered by new technologies to increase our knowledge of islet innervation and its contributions to metabolic regulation. Graphical abstract

Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counterregulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia-associated autonomic failure (HAAF). The mechanisms leading to these blunted effects are only poorly understood. Here, we report, with ISH, IHC, and the tissue-clearing capability of iDISCO+, that growth hormone releasing hormone (GHRH) neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show that low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production, and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule mitochondrial division inhibitor-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, significantly broaden our understanding of the structure of GHRH neurons, and reveal that mitochondrial dynamics play an important role in HAAF. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent HAAF in patients with diabetes.

Three-dimensional mapping of pancreatic innervation shows rapid remodeling of islet innervation in mouse and human diabetes.

This is a protocol for iDISCO Clearing and immunostaining of pancreata/intrapancreatic ganglia in mice.

Hypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counter-regulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia unawareness. The mechanisms leading to these blunted effects remain incompletely understood. Here, we identify, with in situ hybridization, immunohistochemistry and the tissue clearing capability of iDisco, that GHRH neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo . Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule, mdivi-1, we preserved hypoglycemia sensitivity in vitro and in vivo . Our findings present possible mechanisms for the blunting of the CRR, broaden significantly our understanding of the structure of GHRH neurons and for the fist time, propose that mitochondrial dynamics play an important role in hypoglycemia unawareness. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent hypoglycemia unawareness in diabetic patients.